Products and methods for brachytherapy

ABSTRACT

Radioactive sources, preferably radioactive seeds, for use in brachytherapy comprising a radioisotope within a sealed biocompatible container, wherein at least one part of a surface of the container is roughened, shaped or otherwise treated so that it is no longer smooth. The surface treatment may enhance the ultrasound visibility of the source and/or reduce the tendency of the source to migrate once implanted in a patient&#39;s body. Preferred radioisotopes are palladium-103 and iodine-125.

This application is a continuation of U.S. application Ser. No.09/831,229 filed May 4, 2001, which, in turn, claims priority toPCT/GB99/03668, filed Nov. 5, 1999 which is a continuation-in-part ofU.S. Provisional Patent Application Ser. No. 60/107,406, filed Nov. 6,1998.

This invention relates to radiotherapy. More particularly, it relates toradioactive sources for use in brachytherapy, and in particular toradioactive sources with improved ultrasound imaging visibility.

Brachytherapy is a general term covering medical treatment whichinvolves placement of a radioactive source near a diseased tissue andmay involve the temporary or permanent implantation or insertion of aradioactive source into the body of a patient. The radioactive source isthereby located in proximity to the area of the body which is beingtreated. This has the advantage that a high dose of radiation may bedelivered to the treatment site with relatively low dosages of radiationto surrounding or intervening healthy tissue.

Brachytherapy has been proposed for use in the treatment of a variety ofconditions, including arthritis and cancer, for example breast, brain,liver and ovarian cancer and especially prostate cancer in men (see forexample J. C. Blasko et al., The Urological Clinics of North America,23, 633-650 (1996), and H. Ragde et al., Cancer, 80, 442-453 (1997)).Prostate cancer is the most common form of malignancy in men in the USA,with more than 44,000 deaths in 1995 alone. Treatment may involve thetemporary implantation of a radioactive source for a calculated period,followed by its subsequent removal. Alternatively, the radioactivesource may be permanently implanted in the patient and left to decay toan inert state over a predictable time. The use of temporary orpermanent implantation depends on the isotope selected and the durationand intensity of treatment required.

Permanent implants for prostate treatment comprise radioisotopes withrelatively short half lives and lower energies relative to temporarysources. Examples of permanently implantable sources include iodine-125or palladium-103 as the radioisotope. The radioisotope is generallyencapsulated in a titanium casing to form a “seed” which is thenimplanted. Temporary implants for the treatment of prostate cancer mayinvolve iridium-192 as the radioisotope.

Recently, brachytherapy has also been proposed for the treatment ofrestenosis (for reviews see R. Waksman, Vascular Radiotherapy Monitor,1998, 1, 10-18, and MedPro Month, January 1998, pages 26-32). Restenosisis a renarrowing of the blood vessels after initial treatment ofcoronary artery disease.

Coronary artery disease is a condition resulting from the narrowing orblockage of the coronary arteries, known as stenosis, which can be dueto many factors including the formation of atherosclerotic plaqueswithin the arteries. Such blockages or narrowing may be treated bymechanical removal of the plaque or by insertion of stents to hold theartery open. One of the most common forms of treatment is percutaneoustransluminal coronary angioplasty (PTCA)—also known as balloonangioplasty. At present, over half a million PTCA procedures areperformed annually in the USA alone. In PTCA, a catheter having aninflatable balloon at its distal end is inserted into the coronaryartery and positioned at the site of the blockage or narrowing. Theballoon is then inflated which leads to flattening of the plaque againstthe artery wall and stretching of the artery wall, resulting inenlargement of the intraluminal passage way and hence increased bloodflow.

PTCA has a high initial success rate but 30-50% of patients presentthemselves with stenotic recurrence of the disease, i.e. restenosis,within 6 months. One treatment for restenosis which has been proposed isthe use of intraluminal radiation therapy. Various isotopes includingiridium-192, strontium-90, yttrium-90, phosphorous-32, rhenium-186 andrhenium-188 have been proposed for use in treating restenosis.

Conventional radioactive sources for use in brachytherapy includeso-called seeds, which are smooth sealed containers or capsules of abiocompatible material, for example of metals such as titanium orstainless steel, containing a radioisotope within a sealed chamber butpermitting radiation to exit through the container/chamber walls (U.S.Pat. No. 4,323,055 and U.S. Pat. No. 3,351,049). Such seeds are onlysuitable for use with radioisotopes which emit radiation which canpenetrate the chamber/container walls. Therefore, such seeds aregenerally used with radioisotopes which emit γ-radiation or low-energyX-rays, rather than with β-emitting radioisotopes.

In brachytherapy, it is vital to the therapeutic outcome for the medicalpersonnel administering the treatment to know the relative position ofthe radioactive source in relation to the tissue to be treated, toensure that the radiation is delivered to the correct tissue and that nolocalized over or under dosing occurs. Current seeds therefore typicallyincorporate a marker for X-ray imaging such as a radiopaque metal (e.g.silver, gold or lead). Location of the implanted seed is then achievedvia X-ray imaging, which exposes the patient to an additional radiationdose. Such radiopaque markers are typically shaped so that imaging givesinformation on the orientation as well as location of the seed in thebody, since both are necessary for accurate radiation dosimetrycalculations.

Permanent implantation of brachytherapy radioactive sources for thetreatment of, for example, prostate cancer may be done using an openlaparotomy technique with direct visual observation of the radioactivesources and the tissue. However, the procedure is relatively invasiveand often leads to undesirable side effects in the patient. An improvedprocedure comprising the insertion of radioactive sourcestransperineally into predetermined regions of the diseased prostategland using an external template route to establish a reference pointfor implantation has been proposed (see for example Grimm, P. D., etal., Atlas of the Urological Clinics of North America, Vol. 2, No. 2,113-125 (1994)). Commonly, these radioactive sources, for example seeds,are inserted by means of a needle device while an external depth gaugeis employed with the patient in the dorsal lithotomy position. Forprostate cancer treatment, typically 50 to 120 seeds are administeredper patient in a 3-dimensional array derived from multiple needleinsertions of linear, spaced seeds. The dose calculation is based onthis complex 3-D array, plus data on the tumour volume plus prostatevolume etc.

Preferably, the insertion or implantation of a radioactive source forbrachytherapy is carried out using minimally-invasive techniques suchas, for example, techniques involving needles and/or catheters. It ispossible to calculate a location for each radioactive source which willgive the desired radiation dose profile. This can be done usingknowledge of the radioisotope content of each source, the dimensions ofthe source, an accurate knowledge of the dimensions of the tissue ortissues in relation to which the source is to be placed, plus aknowledge of the position of said tissue relative to a reference point.The dimensions of tissues and organs within the body for use in suchdosage calculations may be obtained prior to placement of theradioactive source by using conventional diagnostic imaging techniquesincluding X-ray imaging, magnetic resonance imaging (MRI) and ultrasoundimaging. However, difficulties may arise during the radioactive sourceplacement procedure which may adversely affect the accuracy of theplacement of the source if only pre-placement images are used to guidethe source placement. For example, tissue volume may change as a resultof swelling or draining of fluid to and from the tissue. Tissue positionand orientation can change in the patient's body relative to a selectedinternal or external reference point as a result of for examplemanipulation during surgical procedures, movement of the patient orchanges in the volume of adjacent tissue. Thus, it is difficult toachieve accurate placement of sources to achieve a desired dosageprofile in brachytherapy using only knowledge of tissue anatomy andposition that was obtained prior to the placement procedure. Therefore,it is advantageous if real-time visualisation of both the tissue and theradioactive source can be provided. A particularly preferred imagingmethod due to its safety, ease of use and low cost, is ultrasoundimaging.

During the placement of the radioactive sources into position, a surgeoncan monitor the position of tissues such as the prostate gland using,for example, transrectal ultrasound pulse-echo imaging techniques whichoffer the advantage of low risk and convenience to both patient andsurgeon. The surgeon can also monitor the position of the relativelylarge needle used in implantation procedures using ultrasound. Duringthe implantation or insertion procedure, the location of the source maybe inferred to be proximal to the tip of the needle or other device usedfor the procedure. However, the relative location of each separateradioactive source should be evaluated subsequent to the implantationprocedure to determine if it is in a desired or undesired location andto assess the uniformity of the therapeutic dose of radiation to thetissue. Radioactive sources may migrate within the tissue followingimplantation. However, the relatively small size of currentbrachytherapy radioactive sources and the specular reflection propertiesof their surfaces makes them very difficult to detect by ultrasoundimaging techniques, especially when they are orientated in directionsother than substantially orthogonal to the incident ultrasound beam.Even very small deviations from 90E relative to the incident ultrasoundbeam cause substantial reductions in the intensity of the echo signal.

The ultrasound visibility of conventional radioactive seeds is highlydependent upon the angular orientation of the seed axis with respect tothe ultrasound inducer used for imaging. A smooth flat surface willgenerally act as a mirror, reflecting ultrasound waves in the wrongdirection unless the angle between the sound and the surface is 90E. Asmooth cylindrical structure such as a conventional radioactive seedwill reflect waves in a fan shaped conical pattern spanning aconsiderable spatial angle but will only give strong ultrasoundreflections when imaged at an angle very close to 90E. One way ofimproving the ultrasound visibility of conventional radioactive seeds istherefore to reduce the angular dependence of the reflected ultrasound.

There is therefore a need for radioactive sources for use inbrachytherapy with improved ultrasound imaging visibility, and inparticular for sources where the dependence of visibility on the angularorientation of the axis of the source with respect to the ultrasoundtransducer is reduced.

Ultrasound reflections may be either specular (mirror-like) or scattered(diffuse). Biological tissue typically reflects ultrasound in ascattered manner, whilst metallic devices tend to be effectivereflectors of ultrasound. Relatively large smooth surfaces such as thoseof needles used in medical procedures reflect sound waves in a specularmanner.

Efforts have been made to enhance the ultrasound visibility ofrelatively large surgical apparatus, such as surgical needles, solidstylets and cannulae by suitable treatment of their surfaces such asroughening, scoring or etching. Thus, U.S. Pat. No. 4,401,124 disclosesa surgical instrument (a hollow needle device) that has a diffractiongrating inscribed on the surface to enhance the reflection coefficientof the surface. Sound waves that strike the grooves are diffracted orscattered as secondary wave fronts in many directions, and a percentageof those waves are detected by the ultrasound transducer. Thediffraction grating is provided for use at the leading edge of asurgical instrument for insertion within a body or for use along asurface of an object the position of which is to be monitored while inthe body.

U.S. Pat. No. 4,869,259 discloses a medical needle device that has aportion of its surface particle-blasted to produce a uniformly roughenedsurface that scatters incident ultrasound such that a portion of thescattered waves is detected by an ultrasound transducer.

U.S. Pat. No. 5,081,997 discloses surgical instruments with soundreflective particles imbedded in a portion of the surface. The particlesscatter incident sound, and a portion is detected by an ultrasoundtransducer.

U.S. Pat. No. 4,977,897 discloses a tubular cannula device comprising aneedle and an inner stylet in which one or more holes are cross-drilledperpendicular to the axis of the needle to improve ultrasoundvisibility. The solid inner stylet may be roughened or scored to enhancethe sonographic visibility of the needle/stylet combination.

WO 98/27888 describes a echogenically enhanced medical device in which aprint pattern mask of non-conductive epoxy-containing ink istransfer-coated to the surface of the device, flash dried, and thenthermally crosslinked. Portions of the needle not protected by the maskare removed by etching in an electropolishing step to leave a pattern ofsubstantially square depressions in the bare metal, and the ink maskedis removed with a solvent and mechanical scrubbing. The depressionsprovide the device with enhanced echogenicity under ultrasound.

U.S. Pat. No. 4,805,628 discloses a device which is inserted orimplanted for long-term residence in the body, which device is made morevisible to ultrasound by providing a space in the device which has asubstantially gas impermeable wall, such space being filled with a gasor mixture of gases. The invention is directed to IUD's (intrauterinedevices), prosthetic devices, pacemakers, and the like.

McGahan, J. P., in “Laboratory assessment of ultrasonic needle andcatheter visualization.” JOURNAL OF ULTRASOUND IN MEDICINE, 5(7), 373-7,(July 1986) evaluated seven different catheter materials for theirsonographic visualisation in vitro. While five of the seven cathetermaterials had good to excellent sonographic detection, nylon andpolyethylene catheters were poorly visualised. Additionally, variousmethods of improved needle visualisation were tested. Sonographic needlevisualisation was aided by a variety of methods including eitherroughening or scoring the outer needle or inner stylet and placement ofa guide wire through the needle.

However, none of the above-mentioned prior art discloses or suggestsmethods for improving the ultrasound visibility of radioactive sourcesfor use in brachytherapy, including the relatively much smallerradioactive sources or seeds for use in permanent implants, nor the needto provide improved ultrasound visibility of such sources. Indeed, thereis a bias in the brachytherpay field against changing the seed capsuledesign, since it has been essentially unchanged and has continued to becommercially successful for over 20 years, tpgether with the fact thatany such change may have Regulatory or nuclear safety implications, andwould hence typically be avoided. In addition, any such change could beviewed as increasing the liklihood of problems with the seeds ‘sticking’in needles etc., i.e. it is viewed as highly desirable that the seedsmove smoothly within needles, cannulae etc. “Sticking” of seeds withinloading devices is a known problem for clinicians and can present asafety risk. Thus, if undue pressure is applied to move a stuck seed, itis known that the seed capsule may rupture with consequent radioactiverelease, contamination etc. Hence, there is a bias in the art towardsmaking seeds smoother (or at least having less friction) rather thanseemingly the other way round.

Once implanted, seeds are intended to remain permanently at the site ofimplantation. However, individual seeds may on rare occasions migratewithin a patient's body away from the initial site of implantation orinsertion. This is highly undesirable from a clinical perspective, forexample as it may lead to underdosing of a tumour or other diseasedtissue and/or exposure of healthy tissue to radiation. There istherefore also a need for radioactive sources for use in brachytherapywhich show a reduced tendency to migrate within a patient's body whencompared to conventional brachytherapy seeds.

According to one aspect of the present invention there is thereforeprovided a radioactive source for use in brachytherapy comprising aradioisotope within a sealed biocompatible container, wherein at leastone part of a surface of the container is roughened, shaped or otherwisetreated such that it is no longer smooth. The surface treatment mayenhance the ultrasound visibility of the source and/or reduce thetendency of the source to migrate once implanted in a patient's body.

Suitable radioisotopes for use in the radioactive brachytherapy sourcesof the invention are known in the art. Particularly preferredradioisotopes include palladium-103 and iodine-125.

Suitable carriers for the radioisotope within the biocompatiblecontainer may comprise materials such as plastics, graphite, zeolites,ceramics, glasses, metals, polymer matrices, ion-exchange resins orother, preferably porous materials. Alternatively, the carrier may bemade of metal, e.g. silver or may comprise a layer of metal plated ontoa suitable substrate. Suitable substrate materials include a secondmetal such as gold, copper or iron, or solid plastics such aspolypropylene, polystyrene, polyurethane, polyvinylalcohol,polycarbonate, Teflon™, nylon, delrin and Kevlar™. Suitable platingmethods are known in the art and include chemical deposition,sputtering, ion plating techniques, electrodeless plating andelectrodeposition.

The carrier material may be in the form of a bead, wire, filament orrod. Such carrier materials may be encapsulated in a hollow sealedcontainer, for example a metal container, to provide a sealed source or“seed”, or the carrier may be coated with an electroplated shell, forexample a layer of a metal such as silver or nickel. The radioisotopemay be physically trapped in or on the carrier, for example byadsorption, or may be chemically attached to it in some way.Alternatively, the source may comprise a hollow sealed containerdirectly encapsulating the radioisotope without the need for a carrier.

Suitable biocompatible container materials include metals or metalalloys such as titanium, gold, platinum and stainless steel; plasticssuch as polyesters and vinyl polymers, and polymers of polyurethane,polyethylene and poly(vinyl acetate), the plastics being coated with alayer of a biocompatible metal; composites such as composites ofgraphite, and glass such as matrices comprising silicon oxide. Thecontainer may also be plated on the outside with a biocompatible metal,for example gold or platinum. Titanium and stainless steel are preferredmetals for such containers, especially titanium.

The radioisotope may also be incorporated into a polymer matrix, or aplastic or ceramic composite, and/or may form part of a container wall.For example, if a metal alloy is used to form a container, then acomponent of the alloy may be a suitable radioisotope. If a container ismade from a composite material, a component of the composite may be asuitable radioisotope.

The source should be of an overall size and dimensions suitable for itsintended use. For example, the overall dimensions are preferably suchthat the source can be delivered to the treatment site usingconventional techniques, for example using a hollow needle or acatheter. Seeds for use in the treatment of prostate cancer are, forexample, typically substantially cylindrical in shape and approximately4.5 mm long with a diameter of approximately 0.8 mm, such that they maybe delivered to the treatment site using a hypodermic needle. For use inthe treatment of restenosis, a source should be of suitable dimensionsto be inserted inside a coronary artery, for example with a length ofabout 10 mm and a diameter of about 1 mm, preferably a length of about 5mm and a diameter of about 0.8 mm, and most preferably with a length ofabout 3 mm and a diameter of about 0.6 mm. Sources for use in thetreatment of restenosis are typically delivered to the treatment siteusing conventional catheter methodology. The sources of the inventionmay also be substantially spherical in shape.

The sources of the invention may be used as permanent implants or fortemporary insertion into a patient. The choice of radioisotope and typeof source, plus the method of treatment used, depends in part on thecondition to be treated.

As used herein, the term “roughened, shaped or otherwise treated” meansa surface or part surface which is not smooth and polished as in regularor conventional brachytherapy sources but which comprises irregularitiesor discontinuities of some kind. The irregularities or discontinuitiesmay be arranged in a regular pattern or may be random, or there may bepresent a mixture of random and regular regions. The irregularities ordiscontinuities may take the form of grooves, scratches, abrasions,depressions or the like incised, pressed, stamped, etched or otherwisescored into a surface. The irregularities or discontinuities may alsotake the form of ridges, bumps, undulations or the like upstanding froma surface.

If a source with improved ultrasound visibility is required, theroughening, shaping or other treatment should be over a sufficientportion of the surface of the container that the scattering ofultrasound by the source is substantially omnidirectional. Theroughening, shaping or other treatment may occur over substantially theentire surface of the container, at one or both ends, in the centre orover any other portion of the surface. Preferably, the roughening,shaping or other treatment is such that the source will be visible toultrasound in substantially all orientations relative to the incidentbeam.

For improved ultrasound visibility, the size of the irregularities ordiscontinuities on the surface of the containers (such as rods,spheroids, canisters, seeds and the like) should be such that theultrasound imaging visibility of the sources is improved over that of asimilar source with a smooth surface. Preferably, each individualirregularity reflects and/or scatters ultrasound in an omnidirectionalmanner. Typically, the irregularities will be of an amplitude up toapproximately one quarter of a wavelength of the ultrasound involved inwater. At an ultrasound frequency of 7.5 MHz, this is about 50 μm forexample 40-60 μm. Depending on the frequency of the ultrasound,amplitudes of about 30 to about 90 μm may be suitable. Within this sizerange, larger irregularities are preferred due to an increase inreflected energy. Lower amplitudes, for example below about 20 μm, maynot provide significant enhancement of ultrasound visibility.

The roughening, shaping or other treatment may take the form ofproduction of grooves, depressions, scratches or the like on a surfaceof the container. The grooves etc may be arranged randomly on thesurface or in more regular patterns, for example in geometric shapes andpatterns such as squares and circles, or as lines running substantiallyparallel or perpendicular to an axis of the source, or in a helicalarrangement. Preferably, the grooves etc are not arranged in a highlyrepeating pattern with more than 1 repeat per quarter wavelength as suchpatterns may act as optical gratings and lead to a loss ofomnidirectionality in the echo return. Suitable roughening, shaping orother treatment will depend in part on the exact size and shape of theradioactive source concerned, and can be readily determined using trialand error experiments.

Preferably, the irregularities or discontinuities are in the form of ahelical groove (e.g. with a sinusoidal profile) on the surface of thecontainer. The pitch of the helix may be chosen to give first ordermaxima in the intensity of the reflected ultrasound at certain specificangles with respect to the orthogonal orientation. For example, for aconventional radioactive seed 4.5 mm long and 0.8 mm in diameter, apitch of about 0.6 mm will give a maximum at 10E from orthogonal with7.5 MHz ultrasound, whilst a pitch of about 0.3 mm will give a maximumat 20E from orthogonal. For such a seed the depth of the groove frompeak to bottom should be approximately 40 to 60 μm. The spacing ofrepetitive grooves along a source's axis should not be too close,otherwise a minimum of ultrasound scattering may occur at angles closeto 90E (i.e. orthogonal).

Preferably, the source will comprise a radiopaque substance, for examplesilver or another metal, such that the sources may be visualised usingX-ray imaging techniques in addition to ultrasound imaging.

Preferred sources of the invention are sources comprising a metalcontainer or capsule encapsulating a radioisotope, with or without acarrier, which can be visualised by both ultrasound and X-ray imagingtechniques.

One advantage of using the sources of the invention in brachytherapy isthat the ultrasound signal and image may be read, measured and analysedby suitable computer software sufficiently quickly to allow a physicianto plan real-time dosimetry. This is advantageous from a clinical viewpoint for both patient and medical personnel. However, the sources ofthe invention may be used in processes involving any type of dosimetrymapping that uses information obtained due to the ultrasound visibilityof the sources.

In addition, a physician may use the same imaging technique, i.e.ultrasound, already in place during surgery to confirm both organ (e.g.prostate) position and size, and source placement. This could enable aphysician to calculate if additional sources need to be inserted, forexample in situations where the dose pattern needs to be recalculatedbased on the “real” position of the seeds.

The radioactive sources of the invention may be supplied within asubstantially linear biodegradable material, for example as in theproduct RAPIDStrand™ available from Medi-Physics, Inc. of Illinois,U.S.A. Preferably the sources are evenly spaced (e.g. 10 mm apart inRAPIDStrand™) to permit more even/uniform radiation dosimetry and thedimensions of the array are such that the whole can be loaded into aneedle for administration to a patient. The biodegradable material maybe a suture or a suitable biocompatible polymer.

The roughened, shaped or otherwise treated surface of a source of theinvention may be produced by a variety of different methods. In afurther aspect of the invention, there is provided a method forincreasing the ultrasound visibility of a radioactive source for use inbrachytherapy comprising a radioisotope and a sealed biocompatiblecontainer, the method comprising roughening, shaping or otherwisetreating a surface or part of a surface of the container to therebyprovide irregularities or discontinuities of dimensions and arrangementeffective to enhance reflection of ultrasound to facilitate detectionthereof.

For example, if the source comprises a radioisotope encapsulated in anessentially cylindrical container or an encapsulating material, then theouter surface of the container or encapsulating material may beroughened or shaped by forcing the source through a ridged or serrateddye or a threading device to impart grooves on the surface. A similareffect may be produced by milling. The surface may also be roughened asa result of mechanical friction, for example by use of a wire brush or afile, or a suitable grade of sandpaper, e.g. a coarse grade. The outersurface may also be etched, for example using a laser or water-jetcutter, or by electrolytic etching. Blasting, for example sand blasting,may also be used. Blasting may be done dry, or wet as in water-jetblasting.

If the source comprises an electroplated support, the electroplatingprocess itself may lead to a sufficiently roughened surface for thepurpose of the invention.

Manufacture of radioactive seeds comprising a radioisotope inside asealed metal or metal alloy container usually involves the provision ofa suitable metal tube, one end of which is sealed for example by weldingto form a canister. The radioisotope is then introduced into thecanister and the other end also sealed by for example welding to providea sealed source or seed. Alternatively, a container or canister may beformed by stamping in a press from a core of metal or by casting,moulding or forming a core of molten metal, or by machining or drillinga solid core stock of metal, or by melting and reforming and solidifyingmetal stock or by fastening a cap to the end of a tube by means such aswelding or threading, or by use of heat to expand and then contract thecap on cooling. The outer surface of the container may be roughened,shaped or otherwise treated at any stage of the manufacturing process.For ease of manufacture, the roughening, shaping or other treatmentprocess preferably occurs before loading of the container with theradioisotope, more preferably on the non-radioactive metal tube beforesealing of either end, and most preferably on a long section of metaltubing before it is cut into short segments suitable for use in formingcanisters. The roughening, shaping or other treatment process should notbe such that the integrity of the container is compromised. Preferably,the thickness of the container wall is maintained whilst the overallshape after the treatment process is such that the surface is no longersmooth.

In a still further aspect of the invention, there is provided a methodfor the preparation of a radioactive source comprising a radioisotopeand a biocompatible sealed container at least one part of the surface ofwhich is roughened, shaped or otherwise treated so that it is no longersmooth, the method comprising roughening, shaping or otherwise treatingan exterior surface or part of an exterior surface of the biocompatiblecontainer of the source to thereby provide irregularities ordiscontinuities in the exterior surface.

In a still further aspect of the invention, there is provided a furthermethod for the preparation of a radioactive source comprising aradioisotope and a sealed biocompatible container at least one part ofthe surface of which is roughened, shaped or otherwise treated so thatit is no longer smooth, the method comprising

(i) roughening, shaping or otherwise treating a surface or part of asurface of a biocompatible container material to provide irregularitiesor discontinuities of dimensions;

(ii) loading a radioisotope into the biocompatible container material ofstep (i); and

(iii) sealing the biocompatible container.

For example, a suitable thin-walled metal tube such as a titanium metaltube may be mechanically deformed before insertion of the radioactivematerial and welding of the ends to form a sealed source. A smoothhelical groove may be produced on both the inner and outer surfaces ofthe tube without affecting the thickness of the wall by use of asuitable crimping process. A support tool of cylindrical shape and withouter threads of a suitable pitch and depth may first be inserted intothe metal tube. The support tool should fit tightly within the tube. Acrimping tool may then be applied forcefully to the outer surface of thetube. The shape of the crimping tool should match that of the supporttool. The crimping tool may consist of two or more parts, each partcovering a different sector of the tube's surface. Following thecrimping operation, the support tool may be removed by simply twistingdue to its helical threaded shape.

One or more helical grooves may also be produced by gently pressing asharp metal edge to the surface of a container while the container isrolled over a solid surface at a slight angle, either before or afterthe container is sealed to form a radioactive source.

If improved ultrasound visibility of a source is desired, alternativelyor additionally to roughening, shaping or treatment of the outersurface, the inner surface of the container may be roughened, shaped orotherwise treated prior to introduction of the radioisotope. Forexample, a non-uniform or roughened surface inside a container may beintroduced by means of a tap to create helical or screw threads on theinside of the container. The tap may gouge, score or auger out a threadpattern as it is turned into the container. The spacing of the threadson the inside of a container may be set at any desired dimensionobtainable by tapping the inside of the container. The tapping may bedone before one end is sealed (i.e. on a tubular precursor to thecontainer) or after one end is sealed (i.e. on a can). Preferably, thetubing is scored before it is sealed at one end.

If the inner surface of a container is roughened, shaped or otherwisetreated, the overall thickness of the container wall should not be sogreat that no ultrasound penetrates to the interior of the container andis reflected therefrom. Suitable thicknesses may be readily determinedby experimentation. A thickness of the container wall of up to about 0.1mm is suitable.

The thickness of the wall of a container encapsulating a radioisotope isdependent upon at least the energy of the radioisotope and the nature ofthe carrier. For example, conventional ¹²⁵I sources use 50 μm thicktitanium cylinders for containment which are sufficient to block betaparticles emitted by the ¹²⁵I while letting enough gamma rays and lowenergy X-rays through for therapeutic impact. However, if an aluminumcontainer were used, the wall thickness would need to change in order toadequately capture any beta particles emitted. Correspondingly, if apolymeric container were used, it would need to be coated, for examplewith a titanium oxide “paint” or be plated with a metal to modify orblock beta particle emissions if the plastic itself did not capturethem. Higher energy sources may be used with thicker carriers than lowerenergy sources.

The number of helical or spiral ridges, threads, grooves or the like onan inner or outer surface of a container may be, for example, in therange from about 1 to about 100 per mm of length of the container body.

The tube or container may be incised with at least one ridge, thread orgroove pattern and optionally with more than one such pattern ofdifferent advancing spiral or helical threads which may be in the sameor opposite sense of handedness. The thickness or depth of each suchridge, thread or groove may vary from about 1 μm to about half thethickness of the container wall if desired. Two or more ridges, threadsor grooves of different spacings, different handedness, and/or differentthicknesses or depths may be tapped into the container to give a widevariety of scoring patterns on the inside surface thereof or incisedonto the outer surface of the container to give a wide variety ofscoring patterns on the outside thereof.

The thickness of the container wall may preferably be within thespecifications set for conventional brachytherapy radioactive sourcesand seeds, or it may be selected as the optimum useful in brachytherapyby clinical experimentation. Optionally, the container wall may bethicker than finally desired at the start of the roughening, shaping orother treatment procedure, and excess thickness may be removed duringthe procedure, for example during tapping of the inside of thecontainer.

The roughening or shaping on the outer surface of a container accordingto the invention may take the form of serrations on the surface. Theserrations may be in the form of teeth, steps, notches or projections onthe surface of the container. Such serrations may be grouped on part ofthe surface to form a cluster, and/or may be set in rows on part of thesurface. A serrated tooth has one edge subtended from the surface thatis longer than a second edge that is also subtended from the surface,the two such edges meeting at a common point or peak. The direction ofthe serrated tooth is defined as the direction in the plane of theshorter edge. In another aspect, the edges of the teeth may be ofsimilar length, and the teeth may be substantially symmetrical intwo-dimensions. In another aspect, the teeth may be conical, pyramidalor trigonal or of other geometric shape wherein a point is achieved. Theteeth may be of uniform or non-uniform size, and the teeth may comprisemore than one serrate. When more than one set of serrations is present,they should be spaced apart on the surface of the source and should notall run in the same direction. Preferably, there will be two sets ofserrations on opposite sides of a source, and more preferably running inopposite directions.

The roughening, shaping or other treatment of an outer surface of thesource of the invention may reduce the tendency of the sources tomigrate or move once implanted inside a patient when compared toconventional smooth seeds. Serrations on two or more portions of thesurface of a source are particularly suitable in this respect. Suchserrations may also lacerate tissue during implantation, resulting inthe formation of scar tissue which may also help serve to keep theimplanted source in place. Preferably, the roughening, shaping or othertreatment is sufficient to reduce the tendency of a source to migratebut is not such that the sources cannot be delivered to the treatmentsite using conventional methodology and handling techniques. A suitabledegree of roughening etc. may be found by trial and errorexperimentation.

If the source comprises a container comprising a composite material,then the outer surface of the container may be roughened by exploitingdifferences in the physical properties of the materials comprised in thecomposite. For example, if the composite comprises a blend of polymersthat are phase separated in the blend and have different solubilityproperties in a particular solvent, then the surface may be roughened byexposing it to that solvent and thereby causing part of the blend todissolve. Alternatively, if the composite comprises a polymer and asalt, then exposure to a suitable solvent may dissolve the salt but notthe polymer and thereby cause roughening of the surface.

A container comprising a polymeric or ceramic could be rendered “rough”by entraining particles of water soluble materials within the materialof the container. For example, particles of sodium chloride which aresubstantially insoluble in most polymer melts could be entrained in apolymeric container. Upon exposure to water or simply by placementwithin the tissue of interest, the sodium chloride particles maydissolve leaving a “rough” surface to the container. The resultinghyperosmotic effect around the source may also elicit a physiologicalresponse, which might help serve to anchor the source to a greaterdegree than normal and so avoid subsequent movement of the source.

A ceramic composite container could be prepared from two or moredifferent but compatible ceramic materials such that exposure of thecontainer to acid or base could selectively dissolve one or more of thecarrier components so leading to a suitably roughened surface. Forexample, a combination of aluminum oxide and titanium oxide could affordselective dissolution in strongly basic solutions as aluminum is solubleat very high pH whilst titanium passivates and does not dissolve in suchmedia.

Alternatively, a container may be exposed to a corrosive solution suchthat the surface is corroded in an uneven way to lead to a suitablyroughened surface. For example, stainless steel is susceptible tocrevice corrosion by action of chloride ion in an oxidizing environmentat lower pH values.

Any conventional brachytherapy sources may be roughened, shaped orotherwise treated using the method of the invention to improve theirultrasound imaging visibility. For example, the ultrasound visibility ofthe radioactive seeds disclosed in U.S. Pat. No. 5,404,309, U.S. Pat.No. 4,784,116 and U.S. Pat. No. 4,702,228 could be improved. These seedscomprise a capsule and two radioactive pellets separated by a radiopaquemarker within the capsule. The opaque marker imparts detectability byX-ray imaging of the seeds. Roughening of the surface of such capsulescould be achieved for example by abrasive filing or scratching of thesurface. Furthermore, abrasive roughening could be done exclusively inthe region of the capsule proximal to the opaque marker in each designto thereby impart enhanced ultrasound detectability to the capsule inaddition to detectability by X-ray imaging. The region of the capsulethat is proximal to the radioactive pellets may not be roughened, sothat the thickness of the wall of the capsule remains substantiallyuniform around the radioactive pellets. The dose of radiation receivedfrom such partially roughened capsule when implanted in a patient maytherefore be substantially unchanged from the dose of radiation from acompletely unroughened conventional capsule. Calculation andadministration of the dose of radiation may then be independent of thedepth or extent of the surface roughening in the region of the opaquemarker. Likewise, roughening in the region of the marker may be done indepths and to degrees which may change the thickness of the capsule wallwithout substantially altering the profile of radiation dose received bythe patient.

In a further aspect, the invention also provides a method of treatmentof a condition which is responsive to radiation therapy, for examplecancer, arthritis or restenosis, which comprises the temporary orpermanent placement of a radioactive source comprising a radioisotopewithin a sealed biocompatible container, wherein at least one part of asurface of the container is roughened, shaped or otherwise treated tothereby provide irregularities or discontinuities, at the site to betreated within a patient for a sufficient period of time to deliver atherapeutically effective dose.

The invention will be further illustrated, by way of example, withreference to the following Drawings:

FIG. 1 illustrates one embodiment of a radioactive source according tothe invention;

FIG. 2 illustrates another embodiment of a radioactive source accordingto the invention;

FIG. 3 illustrates a metal tube suitable for use in the production ofone embodiment of a radioactive source according to the invention;

FIG. 4 illustrates a cross-sectional view of the metal tube of FIG. 3during the crimping operation;

FIGS. 5 and 6A to D are ultrasound images of a metal wire and metaltubes roughened using embodiments of the methods of the invention.

FIG. 7A is a picture of a conventional titanium seed casing and FIGS. 7Band 7C are pictures of similar seed casings roughened using embodimentsof the method of the invention. FIG. 7D shows in graphical form thebackscattered intensity as a fucntion of the angle of the seed axis inrelation to the ultrasound beam for the seed casings of FIGS. 7A to C.

FIG. 8 shows in graphical form the backscattered intensity as a functionof the angle of the seed axis in relation to the ultrasound beam for aconventional seed casing and two seed casings modified according to theinvention.

FIG. 1 is a schematic illustration of part of a source 1 with serratededges 2, the serrations running in opposite directions on oppositeedges.

FIG. 2 is a schematic illustration of a sealed source 3 according to oneembodiment of the invention. The source comprises a metal, for exampletitanium, container 4 sealed at both ends 5. The inside and/or outsideon the container has a screw thread 6 etched thereon. The containercontains a silver rod 7 coated with a layer of ¹²⁵I-containing silveriodide. The silver rod 7 is detectable by X-ray imaging techniques.

FIG. 3 illustrates a metal (e.g. titanium) tube 8 which has beensubjected to a crimping operation to form helical groves 9 on theoutside and inside thereof. Such a tube is suitable for use in theproduction of a sealed radioactive source according to the invention.

FIG. 4 illustrates in schematic form a cross section through the metaltube 8 of FIG. 3 during the crimping operation. The tube is crimpedbetween a support tool 10 and a crimping tool 11, made up of fourdifferent segments.

FIGS. 5 and 6A to D are ultrasound images which are discussed in moredetail in the following Examples.

FIGS. 7A to D and 8 will also be discussed in more detail in theExamples.

The invention will be further illustrated with reference to thefollowing non-limiting Examples:

EXAMPLES Example 1

A 12 mm long section of a 0.8 mm diameter copper wire was mechanicallyroughened using pliers with a serrated jaw, but no material was removedform the wire. The ultrasound visibility compared with that of a smooth,unroughened portion of the same wire. The results are shown in FIG. 5,which is a sample B-mode ultrasound image of the wire in a water tankobtained using a Vingmed CFM-750 scanner at 5 MHz.

In FIG. 5, 12 is the 12 mm long roughened portion of the wire; 13 is thebottom edge of the water tank used in the experiment; 14 is a smoothportion of the wire and 15 is a specular reflection from the smooth wiresection at a 90° angle to the incident ultrasound. The brightest regionof the wire in the ultrasound image is the roughened portion,illustrating that the roughening of the invention greatly increasesultrasound visibility.

Similar results are obtained if the surface of a conventional titaniumseed canister is roughened in the same way.

Example 2

A straight, thin (0.1 mm diameter) monofilament nylon wire was mountedin a water bath, and imaged with a Vingmed CFM-750 ultrasound scanner at7.5 MHz. The wire was arranged to run diagonally across the image, at anangle of 45E with respect to the soundbeam direction in the centre ofthe image sector. This wire served as a support for pieces of titaniumtubing that could be moved in and out of the central image field. Thetitanium tubes were those used to form conventional canisters forproduction of brachytherapy seeds (length 5 mm, diameter 0.8 mm, wallthickness 0.05 mm), but without welded ends and the radioactive insert.Images of pieces of tubing with different surface modifications weremade in the exact same location, and without changing the geometry orthe scanner instrument settings. A common feature of all imaged tubesegments are diffraction artefacts at the unclosed ends. Validcomparisons of performance can thus only be made by studying the centralregions of the tubes. Also, a bright halo was seen in the images behindthe tubes, most probably caused by acoustic reverberations inside thetube structure.

The following surface modifications were made: a) fine abrasivegrinding, b) rough abrasive grinding, c) rough deformation with no lossof material, and d) no modifications to the original surface.

FIGS. 6A to D shows the resulting ultrasound images. All modificationsresulted in an improved visibility of the central portion of the seedswhen compared to the non-modified case d). Best performance was observedwith fine grinding, a).

Example 3

Measurement Set-up

A wide band 7.5 MHz transducer (Panametrics V320) was mounted in themeasurement chamber wall. With a transducer diameter of 13 mm and afocal distance of 50 mm this transducer has an acoustic field similar toa typical phased array transducer used in clinical TRUS applications.

A brachytherapy seed was mounted on a holder which could be rotated todefined angles in relation to the direction of the ultrasound beam. Theseed was glued on to the tip of a needle protruding from the specimenholder with cyanoacrylate glue so that the seed's centre of gravitycoincided with the rotational axis of the holder. The angular rotationcould be set with half a degree accuracy, which is of great importancegiven the high angular dependency of the US backscatter. The holdercould also be adjusted by translation to position the seed in the focalpoint of the transducer and fixed throughout the experiments.

The transducer was excited with a wide band pulse from a Panametrics5800 pulser-receiver. The received signal was acquired with a LeCroy9310 oscilloscope and digitised. The sampled radio frequency (RF) signal(fs=50 MHz) was then transferred to a computer for further processing.

Three different seeds were tested; an unmodified seed and two differentmodified seeds. The unmodified seed (A) was identical to a standard seedexcept that it has not loaded with radioactive iodine. The dimensions ofthe seed were 0.8×4.2 mm and the wall thickness of the titanium tube was50 microns. Two similar seeds were modified by gently pressing a sharpmetal edge to the seed surface while the seed was rolled over a solidsurface at a slight angle. The resulting deformation was one or morehelical grooves running along the full length of the seed. One of themodified seeds (B) was placed on very fine sandpaper for friction duringthe deformation and a helical groove of 0.058 mm depth, 0.1 mm width andabout 0.54 mm pitch was produced. The other modified seed (C) was placedon a thin rubber sheet during the deformation and the result was severalfiner helical grooves with about 0.03 mm depth and 0.2 mm groovespacing. FIGS. 7A, 7B and 7C show magnified views of the seeds A, B andC respectively. The images were transferred to an image analysis program(Optimas) for measurements of the deformations. The image processingprogram was calibrated using the undistorted length of the seed as areference and several measurements of groove thickness, width and pitchwere averaged for a representative characterisation of the seed surfacedistortion.

A series of measurements mapping the ultrasound backscatter of each ofthe seeds throughout the full range of incidence angles (−65 to 65degrees) were performed. After accurate positioning at the desiredangle, 10 ultrasound pulses were transmitted at a PRF of 10 Hz and thereceived echoes were digitised and stored. The 10 pulses were averagedcoherently before further processing. Three different methods weretested for estimation of the backscattered echo intensities; a) thesquare of the peak amplitude, b) the integral of the signal in a 0.5microsecond gate around the peak amplitude, and c) the integral of abandpass filtered (5-9 MHz) version of the signal in a 1 microsecondtimegate centred as in b). Method a) best represents the “brightness” ofthe seed in an ultrasound image, while methods b) and c) more nearlyrepresent the overall backscattered energy. The three methods yieldedvery similar results for all seeds and angles and the results of methoda) are used herein. Further, images of envelope detected individualscanlines at different angles were made for visualisation. These imagesdirectly represent what a small section of the image containing the seedwould look like on a normal B-mode image.

The numeric results of the backscattered intensity are presented ingraphical form in FIG. 7D. The intensity at normal incidence (i.e withthe seed axis orthogonal to the ultrasound beam) was very similarbetween the different samples. For the unmodified seed A, thebackscattered intensity dropped off very quickly with increasing angleaway from the normal. At 10 degrees angle in either direction, theintensity had reached a minimum about 23 dB below the level of normalincidence (0 degrees). Judging from those measurements, the seed wouldbe dramatically less visible, if visible at all, at angles exceeding∀2.5 degrees from normal incidence. The backscattered intensityincreased again as the incidence angle approached 60 degrees since thetip of the seed entered the ultrasound beam and sound was reflected offthe rounded seed tip.

The modified seeds B and C had a much less pronounced reduction inbackscattered intensity with increasing incidence angle. The intensitydid not drop more than about 10 dB for either of the two modified seedswithin ∀60 degrees of the incidence angle, and the seeds are thereforeexpected to be visible at a much larger angular range than theunmodified seed. For lower angles, variations in intensities caused byconstructive and destructive interference of the sound reflected on thegroves could be observed. This was more pronounced for seed B as thehelical pattern here was deeper and more defined than for seed C. Thedispersion of scattered energy through larger angles for the modifiedseeds compared to the unmodified seed did not significantly effect thebackscattered intensity at normal incidence.

Example 4

The ultrasound visibility of three types of seed in a prostate phantomwas investigated. The prostate phantom was a commercially availablephantom and seeds were inserted in the phantom using the clinical set-upfor seed implantation: i.e., B&K Panther ultrasound machine using 7.5MHz transrectal ultrasound transducer; MMS treatment planning software;B&K hardware for seed implantation; standard 18 gauge seed-implantationneedles.

Three different seed types were investigated. The reference seeds (ref)were dummy (i.e non-radioactive) seeds corresponding to the seedscommercially available from Medi-Physics, Inc. under model number 6711.Seeds A corresponded to the reference seed modified by the addition offive longitudinally spaced grooves around the central portion of eachseed and seeds AC were prepared in a manner analogous to seed B ofExample 3.

The seeds were implanted at a range of angles relative to the ultrasoundbeam (with 0° corresponding to the long axis of the seed beingorthogonal to the ultrasound beam) and the ultrasound visibility of theimplanted seeds was measured.

FIG. 8 shows the results for the three different types of seed. When theultrasound beam struck a seed within the phantom with a deviation of0E∀2E (i.e.: at exactly 90E to the seed's long axis) there was littledifference between the reference and the modified seeds of theinvention. However, when the seeds were implanted at an angle to theultrasound beam, the modified seeds retained their echogenicity to amuch greater extent than did the reference seeds.

What is claimed is:
 1. A method of real-time visualisation of abrachytherapy seed comprising: (i) implanting a brachytherapy seedhaving at least one part of a container surface roughened, shaped orotherwise treated to impart improved ultrasound visibility in a tissueor organ of interest; (ii) imaging with ultrasound; and (iii) recordingthe position of the implanted brachytherapy seed.
 2. The methodaccording to claim 1, wherein the dependence of visibility of thebrachytherapy seed on the angular orientation of the axis of thebrachytherapy seed with respect to the ultrasound beam is reduced. 3.The method according to claim 1, wherein the brachytherapy seed isvisible to ultrasound in substantially all orientations relative to theincident ultrasound beam.
 4. The method according to claim 1, whereinthe brachytherapy seed is visible to ultrasound when the axis of saidbrachytherapy seed is oriented at any angle in the range 0 degrees to 60degrees with respect to the incident ultrasound beam.
 5. The methodaccording to claim 1, wherein the brachytherapy seed is implanted in aprostate gland.
 6. A method of real-time dosimetry comprising: (i)recording the position of the brachytherapy seed according to the methodof claim 1, and (ii) using the position of the implanted brachytherapyseed so recorded to plan the implant position of one or more additionalbrachytherapy seeds.
 7. The method according to claim 6, wherein thebrachytherapy seed is implanted in a prostate gland.
 8. A method oftreatment of a condition which is responsive to radiation therapy whichcomprises: (i) temporarily or permanently placing a brachytherapy seedin a tissue or organ of interest; and (ii) determining the implantposition of one or more additional brachytherapy seeds by the dosimetrymethod according to claim
 6. 9. A method according to claim 7, whereinthe condition is selected from the group consisting of cancer,arthritis, and restenosis.
 10. A method according to claim 9, whereinthe condition is prostate cancer.